Role of thyroid hormone during early brain development

Abstract

The present comments are restricted to the role of maternal thyroid hormone on early brain development, and are based mostly on information presently available for the human fetal brain. It emphasizes that maternal hypothyroxinemia - defined as thyroxine (T4) concentrations that are low for the stage of pregnancy - is potentially damaging for neurodevelopment of the fetus throughout pregnancy, but especially so before midgestation, as the mother is then the only source of T4 for the developing brain. Despite a highly efficient uterine-placental 'barrier' to their transfer, very small amounts of T4 and triiodothyronine (T3) of maternal origin are present in the fetal compartment by 4 weeks after conception, with T4 increasing steadily thereafter. A major proportion of T4 in fetal fluids is not protein-bound: the 'free' T4 (FT4) available to fetal tissues is determined by the maternal serum T4, and reaches concentrations known to be of biological significance in adults. Despite very low T3 and 'free' T3 (FT3) in fetal fluids, the T3 generated locally from T4 in the cerebral cortex reaches adult concentrations by midgestation, and is partly bound to its nuclear receptor. Experimental results in the rat strongly support the conclusion that thyroid hormone is already required for normal corticogenesis very early in pregnancy. The first trimester surge of maternal FT4 is proposed as a biologically relevant event controlled by the conceptus to ensure its developing cerebral cortex is provided with the necessary amounts of substrate for the local generation of adequate amounts of T3 for binding to its nuclear receptor. Women unable to increase their production of T4 early in pregnancy would constitute a population at risk for neurological disabilities in their children. As mild-moderate iodine deficiency is still the most widespread cause of maternal hypothyroxinemia in Western societies, the birth of many children with learning disabilities may already be preventable by advising women to take iodine supplements as soon as pregnancy starts, or earlier if possible.

A study for maternal thyroid hormone deficiency during the first half of pregnancy in China

“…We did not find any correlation between hypothyroxinaemia and TPOAb in this study, which was consistent with the results from the study of Vaidya [16]. Iodine deficiency might be one of the main causes of hypothyroxinaemia [21]. However, participants with iodine deficiency had been excluded from this study.…”

Novel two-dimensional morphometric maps and quantitative analysis reveal marked growth and structural recovery of the rat hippocampal regions from early hypothyroid retardation

“…In the rat THs deficiency during the suckling period results in marked retardation of brain growth and development (for reviews of earlier literature see Dussault & Ruel, 1987;Lauder, 1983;Paternostro & Meisami, 1993;Timiras, 1988; for reviews of more recent literature see Bernal, 2002;Morreale de Escobar et al, 2004;Santisteban & Bernal, 2005;Smith et al, 2002. Early studies on the effects of thyroid deficiency on brain development focused on structural abnormalities in the cerebral cortex (Eayrs, 1955(Eayrs, ,1966Rabie et al, 1979) and cerebellum (Lauder, 1983;Legrand et al, 1986, Patel & Rabie, 1980.…”

Extended clinical phenotype, endocrine investigations and functional studies of a loss-of-function mutation A150V in the thyroid hormone specific transporter MCT8

“…Of utmost importance is the critical role of thyroid hormones in brain and nervous system development (1). The biological effects of thyroid hormones are mediated through the binding of triiodothyronine (T3) to nuclear receptors, which leads to a change in the interaction of the receptors with T3-responsive elements in regulatory regions of many genes (2,3).…”